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April 11, 2013

A Response to Dr. Mason's "Rebuttal" to Criticisms of His Genomics Medicine Article

Much
of the gene patenting debate has appeared, to experienced patent practitioners,
to be akin to a conversation with Kevin Kline's character in A Fish Called Wanda, or perhaps a
passage from P.G. Wodehouse's The Luck of
the Bodkins. In short, it has been
the tale of doctors, scientists, and legal academics interpreting claims to
isolated DNA in ways both bizarre and unlikely to anyone with any experience in
actually claiming DNA. However, as Dr.
Mason's response illustrates those of us on the patent side of the debate have
contributed to the confusion.

Reviewing
Dr. Mason's assessment of the patents and applications he identified as
encompassing almost the entirety of the human genome reveals two sources of
misunderstanding. The first is between
the disclosure of patent specifications and the claims: while sometimes in
their zeal to provide the broadest disclosure possible, patent practitioners
have been overly expansive in defining the scope of the isolated nucleic acids
that are the subject of their clients' inventions, the claims have typically
been more circumspect. Most claims to
isolated DNA have the canonical structure:

And
there are claims to oligonucleotides, usually dependent on the claimed
sequence:

An oligonucleotide comprising about 15 nucleotides of SEQ ID NO: X.

Considered
in a vacuum, in the context of definitions as illustrated in Dr. Mason's
response, it could be thought that such claims encompass a greater scope than
they actually do. What is missing is
context, both historical and legal, that provides the insights needed to
properly understand the scope of these claims.

The
base canonical form above was developed about thirty years ago, during the age
when "cloning" a DNA molecule that encoded a protein of interest
(erythropoietin, tissue plasminogen activator, blood clotting Factor VIII,
interferon, etc.) was a Herculean feat, and such claims were expressly directed
towards full-length versions of these
genes. In the days before the Human
Genome Project and the vast amount of genetic information it produced, such
cloned genes had but one utility: to
permit the production of recombinant cells that expressed the gene product,
typically to be used as one of the first "biologic" drugs. In order for the claimed DNA molecule to have
that utility, however, what was required almost always was that the full-length
gene be isolated, because truncated proteins could not be expected to have the
desired biological properties (and could have deleterious ones, such as
increased immunogenicity or reduced half-life). Accordingly, such claims do not have the scope Dr. Mason ascribes to
them, because any such claim would be invalidated for failing to have the
necessary utility.

Moreover,
the scope of such claims are extremely narrow, being limited to
isolated DNA molecules that encode the specifically recited amino acid sequence
identified as SEQ ID NO: X. An isolated
human DNA comprising any change in this encoded amino acid sequence is not
exclusive to the patentee and can be performed freely without literal
infringement liability by anyone. (The availability of the doctrine of
equivalents for isolated human DNA claims is severely limited by U.S. Patent
and Trademark Office practice in interpreting the application of 35 U.S.C. §
112(a) to such claims, and by ensuing prosecution history estoppel.)

The significance of this limitation in
scope of isolated DNA claims can be understood by the following example. If the
single change in the amino acid sequence expressly recited in the claim is from
a valine (Val) residue to an isoleucine (Ile) residue, the number of atoms in
the protein would be increased by a mere 3 atoms (the difference in structure
between these two amino acids is a methylene group,-CH2-) out a
total of 50-100,000 atoms in the protein. Yet, even such a molecule
changed to such a small degree would not literally infringe the generic
claim. Similarly, insertions or
deletions of the sequence, mutations and sequence variants (naturally occurring
or man-made) do not fall within the scope of claims to a specific, particular
isolated human DNA, due to this restricted scope. Such claims reciting
such full-length "genes" are simply not preclusive of any other gene
in the genome.

Turning to the oligonucleotide claims,
there are two issues. First, the work of
Bob Cook-Deegan and his collaborators have shown (Kepler et al., "Metastasizing patent claims on BRCA1") that oligonucleotides
on the order of 15-16 nucleotide residues in length are much more ubiquitous in
the genome than was once thought. This
stems from the simplistic and incorrect assumption that any sequence of n nucleotides will occur once per 4n times in the genome. Thus, the random 15-mer was expected to arise
once every 1,073,741,824 basepairs, and the random 16-mer once every
4,294,967,296 basepairs. The (false)
conclusion was that in a haploid genome comprising 3 x 109
basepairs, the 15-mer and 16-mer (and larger species) would be unique. The source of the error is that human DNA is
a historical molecule, and that many sequence motifs would be expected to arise
many more times than random statistics would predict; the Human Genome Project
(and basic biology) illustrates the fact that the human genome evolved by gene
duplication and recombination, so that certain motifs (the ATP-binding cassette
sequences, for example) sharing certain amino acid sequence and thus the
nucleotide sequences encoding them, are much more common that was
predicted. The consequence of this biological fact is not that claims to such
oligonucleotide encompass the entirety of the genome. Rather, it is that claims of this scope are
invalid, since the prior art is much more replete with these sequences than was
expected.

The other distinction that should be
appreciated is that what is disclosed (and even claimed) in patent applications
does not raise infringement issues. Indeed, filing overbroad claims in International Applications can be a
strategic decision, to produce prior art against competitors (this stratagem
became available in the U.S. with publication of U.S. applications under the
American Inventor Protection Act of 1999). Mere inspection of the published patent application database can find
patents to a variety of "inventions" unlikely to ever grant with
patentable claims, and their existence is thus not relevant to a serious debate
over the scope of patents claiming
isolated human DNA.

It is difficult to avoid the conclusion
that a failure to appreciate these distinctions informs much of the angst
enunciated by Dr. Mason and other physicians and researchers confronted by the
prospect of infringement liability (or at least the fear that threats from
patent holders will inhibit progress in genetics research). But the patent community is not entirely blameless
either, as illustrated by Dr. Mason in his Rebuttal. There exists a certain amount of loose
language in patent specifications that creates understandable confusion as to
the claim scope the patentee believes
she is entitled to, and thus uncertainty as to whether claims will be asserted
as broadly as these specifications can be interpreted to support. (Of course, some have interpreted these
claims to encompass isolated DNA itself, an interpretation that would render
the claims unpatentable since the time of Friedrich Miescher's work in the 19th
Century.) Some comfort should be taken
by the fact that no gene patent holder has ever asserted claims to this extent,
and that any attempt to do so would likely result in invalidation of the
claims. And the patent case law has
provided more and more illustrations of claims (including Myriad's method
claims) being interpreted in view of these overbroad specifications and
invalidated based on broad claim construction. In short, while there may be specifications suffering from symptoms of
overbroad disclosure, the disease is self-correcting (even more so with the
post-grant review and inter partes
review provisions of the Leahy-Smith America Invents Act).

What is clearly needed is more dialog (and
perhaps fewer assumptions) from both physicians and the patent community. This debate comes thirty years too late to be
particularly meaningful to claims to isolated nucleic acids. But as the complexities of "modern"
gene-based inventions increase (and their capacity to be ever more resistant to
reverse engineering), the potential to eschew patent protection will increase,
with the concomitant reduction in disclosure of biologically relevant
inventions. Such a trend, and Supreme
Court decisions that promote that trend, particularly if based on unrealistic
apprehensions over the (vanishingly small) possibility that claims to isolated
human DNA will negatively impact developing genetic technologies, could
paradoxically promote the outcome that opponents of gene patenting purportedly
are committed to prevent.

Comments

One other comment. As I noted in my comment below, I agree with you that we patent attorneys share some responsibility for the confusion over what these nucleotide patent claims cover. But what I'm very concerned about is that the views of these scientists, academic or otherwise, on what these nucleotide patent claims cover is being given undue credibility that they frankly don't deserve, be it in court cases or by the popular media. That's my biggest concern and beef here.

I agree. I have seen these "peer-reviewed" articles submitted as exhibits at trial. However, they are not peer-reviewed in the practicing/academic legal community, but the academic/scientific community. Unfortunately, a saying comes to mind: "Great minds think alike, but fools seldom differ."

It is understandable that many scientists, physicians, and lawyers who aren't patent practitioners tend to misinterpret the meaning of patent claims. It is baffling, however, that they are bold enough to publish on a topic they do not understand. Nevertheless, the public listens to them.

Another critical point they don't seem to understand is that secrecy is often the next best alternative for any category of technology where patent protection is stripped away (Kevin's reference in the last sentence). I wonder how long it would have taken for others to figure out PCR if Cetus had kept it secret rather than patented?

Very interesting discussion and right on point. But of course, I am a patent practioner who has been involved with patenting isolated polynucleotides for the last 20 years. The question in my mind is: how can the Supreme Court exclude "gene patenting" (as understood by the lay press) without diluting investments in other technologies ? If there is reason to exclude patenting polynucleotides that have corresponding sequence in nature, isn't that for Congressional action and not the Court ?

In theory they could render a very narrow decision based on the uniqueness of human DNA (akin to Judge Sweet's opinion distinguishing DNA from other biomolecules) that might leave DNA from other organisms patent eligible.

And while you are right that this should be up to Congress, the Court is exercising its supervisory powers to ensure that the PTO is executing laws falling within Congress's power to enact.

Kevin, I agree that more dialogue (and fewer assumptions) are needed to come to an understanding, especially in the science community, about what these patents cover and what rights they confer.
I think there is more going on here than a lack of dialogue and mistaken assumptions, however. Dr. Mason did not disclose his active involvement in the Myriad litigation, and he openly sought to influence the outcome of the pending Supreme Court case both in his paper and elsewhere. He has been researching this question for years and has been interacting with the lawyers (some of them patent lawyers) at PUBPAT and the ACLU. Given his longstanding professional involvement with the issue, I find it, frankly, hard to understand how he could now misunderstand the operation and meaning of patent claims in ways that allowed him to reach such a convenient result at such a convenient time. The ACLU made repeated reference to his recent paper in its reply brief to the Supreme Court. And his article was actively played to the popular press at a strategic point in time.

Kevin,
Thanks for a very interesting article. Couple of comments as a scientist who does not practice law:
Although you make the point that an important part of "gene patents" is the capability to produce the full-length protein for use as a diagnostic or therapeutic, the claims related to 15-mer DNA molecules are also very important. Two DNA molecules 15-25 nucleotides in length are required for PCR amplification of a gene (potentially useful as a precursor to sequencing of portions of a gene). Likewise, a single short DNA molecule is used to initiate Sanger sequencing of a gene. Slightly longer DNA molecules (often between 25 and 60-mer) are attached to a solid support (microarrays, for instance) for analysis of gene expression and for analysis of DNA copy number. As a result, I find claims 5 and 6 of '282 to be quite worrisome.

To address that, I turn to your discussion of Kepler et al. Quoting from above:
"Rather, it is that claims of this scope are invalid, since the prior art is much more replete with these sequences than was expected."

If one can demonstrate a single nucleotide sequence deposited prior to the BRCA1 discovery that contains a 15-mer in common with the BRCA1 coding sequence (likely), would a court likely invalidate '282 claims 5 and 6 completely? Or as an alternative, would the claim be whittled down to those DNA molecules that were novel at the time of filing?

I would hope that '282 claim 16 could also be invalidated under similar grounds. It could be construed to apply to PCR pairs for much of the chromosome 17.

I suppose one way to address the question is to ask whether companies like Affymetrix (which are producing commercial oligo arrays) have been sued or required to license any primers that were not explicitly claimed. And, of course, to determine whether these were "unique" as that term is now understood with regard to distribution in the human genome.

More to the point, while we might envision interpretations whereby a company could initiate a lawsuit, the fact that no one has is a reminder that companies don't do so lightly.

We don't inquire about Prof. Mason's motives (the ACLU's and PubPat's are clear), mostly because they are irrelevant to this discussion. (If asked, perhaps Myriad's lawyers could refer the Justices to our blog discussion.).

What's important here is that the Professor identify his grounds and bases for his conclusions, and for us to address them. I think in fairness a reader will understand that Prof. Mason's conclusions are at least ill-considered.